Recent studies demonstrate the presence of a calcium receptor protein on parathyroid cell that enables these cells to detect and respond to changes in the concentration of extracellular calcium. Drugs that act on this receptor to mimic the effects of extracellular calcium would offer a novel therapeutic approach to the treatment of hyperparathyroidism. In Phase I studies, it was shown that certain organic compounds were able to act on the calcium receptor and inhibit parathyroid hormone secretion. In Phase II, the proposal is to establish a data base that defines the structural features of compounds that contribute to activity on the calcium receptor. This will be obtained by limited structure-activity studies on compounds shown to be effective in Phase I studies and by testing of selected natural product compounds. It is also proposed to clone the calcium receptor cDNA in order to obtain structural information about the receptor and to create transfected cell lines necessary for high-throughput screening of natural product libraries. The proposed studies, which constitute the first description of the pharmacology and structure of the calcium receptor, will provide the technologies enabling a drug development program aimed at the discovery and design of drug candidates for the treatment of hyperparathyroidism.